Long-term survivors of acute lymphoblastic leukemia(ALL) frequently demonstrate measurable deficits in cognitive functioning due to neurotoxicity of intensive, curative chemotherapy. Deficits occur at rates exceeding siblings and age-matched controls, negatively impacting school and occupational performance, and diminishing quality of life. Development of clinical trials to test protective interventions is dependent upon first identifying those subjects who are most vulnerable to experiencing treatment-induced cognitive dysfunction, both during and after treatment for leukemia. This proposal takes a novel approach to overcome this obstacle. The main objective of this research is to identify markers of specific treatment-induced decline in cognitive functions to differentiat children who are at greatest risk for exhibiting cognitive deficits in the years following completin of treatment. To do this, we will use non-invasive computer-based cognitive assessments to document treatment-induced changes in neurocognitive functioning at multiple specific time points during the early phases of therapy (Aim 1) and link the measured changes in working memory, associative learning, and executive functions to changes in biomarkers within cerebrospinal fluid collected from the same patients (Aim 2).The results of this project will enable us to identify patients experiencing subclinical changes in cognitive function early in therapy, and link them to biomarkers that will shed light on the underlying pathophysiology. This contribution is significant because if subclinical changes in neurocognitive function can be reliably demonstrated during the early stages of therapy, and linked to deficits in cognitive function after the conclusion of therapy, it would be possible to test preventive strategies specifically targeting those children at increased risk for persistent cognitive deficits post-treatment. The results are thus expected to have a positive impact because they will provide the foundation to improve the therapeutic index of cancer therapy, and potentially guide clinical trials of protective interventions aimed at reducing the permanent burdens of curative treatment for leukemia.